| Autor: |
Lewis KE; Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA., Selby MJ; Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA., Masters G; Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ., Valle J; Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA., Dito G; Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ., Curtis WR; Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA., Garcia R; Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA., Mink KA; Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA., Waggie KS; Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA., Holdren MS; Drug Safety Evaluation, Bristol-Myers Squibb, Mt. Vernon, IN., Grosso JF; Early Clinical Development, Bristol-Myers Squibb, Princeton, NJ., Korman AJ; Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA., Jure-Kunkel M; Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ., Dillon SR; Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA. |
| Abstrakt: |
Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of immune-modulatory interleukin-21 (IL-21) combined with checkpoint blockade in several syngeneic mouse tumor models. After tumor establishment, mice were administered recombinant mouse IL-21 (mIL-21) alone or in combination with blocking monoclonal antibodies against mouse PD-1 or CTLA-4. In contrast to monotherapy, IL-21 enhanced antitumor activity of mCTLA-4 mAb in four models and anti-PD-1 mAb in two models, with evidence of synergy for one or both of the combination treatments in the EMT-6 and MC38 models. The enhanced efficacy was associated with increased intratumoral CD8+ T cell infiltrates, CD8+ T cell proliferation, and increased effector memory T cells, along with decreased frequency of central memory CD8+ T cells. In vivo depletion of CD8+ T cells abolished the antitumor activities observed for both combination and monotherapy treatments, further supporting a beneficial role for CD8+ T cells. In all studies, the combination therapies were well tolerated. These results support the hypothesis that the combination of recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies could lead to improved outcomes in cancer patients. |
